High-resolution immune-profiling in ovarian cancer

Le carcinome séreux de haut grade (CSHG) est le sous-type de cancer de l'ovaire le plus agressif et mortel. Alors qu'une meilleure survie globale des patientes soit associée à une infiltration lymphocytaire, l'immunothérapie par blocage des points de contrôle immunitaires a obtenu des résultats limités, témoignant ainsi l'importance de comprendre le fonctionnement du système immunitaire au sein de ces tumeurs malignes. L’immunologie des tumeurs intègre des cellules immunitaires innées et adaptatives et utilise des médiateurs inflammatoires pour ajuster finement l'ampleur et la durée de la réponse immunitaire. Ainsi, cette thèse a pour objectif de définir l'hétérogénéité des cellules immunitaires intratumorales et périphériques chez les patientes atteintes d'un cancer de l'ovaire mais aussi à explorer les mécanismes de la réponse immunitaire. En combinant des techniques de biologie computationnelle et de séquençage de l'ARN à cellule unique nous avons pu identifier les différents composants du système immunitaire des patientes atteintes d'un cancer de l'ovaire mais aussi valider nos résultats dans une plus large cohorte associant d'autres types de cancer. Dans un premier temps, nous avons étudié l'un des médiateurs de l'inflammation, la voie de signalisation extracellulaire de l'adénosine. Nous avons évalué l'impact de cette voie de signalisation sur la survie des patientes atteintes de CSHG et identifié les cellules du microenvironnement tumoral participant au fonctionnement de cette voie. Ensuite, nous avons concentré notre étude sur la dynamique des lymphocytes T et identifié leurs états cellulaires associés, déduit leur relation développementale et étudié les changements transcriptionnels déclenchés par les interactions entre les cellules dans le microenvironnement immunitaire tumoral. Nous avons démontré que les cellules de type Tfh produisent le médiateur 7α,25 dihydroxycholestérol (7α,25-HC) décrit comme régulant le positionnement des cellules immunitaires dans les organes lymphoïdes secondaires. Ainsi, notre étude suggère que les cellules de type Tfh utilise ce mécanisme pour recruter des lymphocytes T CD8 pré-effecteurs/prédysfonctionnels et des cellules dendritiques plasmacytoïdes dans les tumeurs. Finalement, nos résultats indiquent que les cellules de type Tfh exprimant l'interleukine-21 aident à promouvoir l'immunité antitumorale contre les tumeurs ovariennes en coordonnant l'action des lymphocytes et des cellules dendritiques plasmacytoïdes sensibles au 7α,25-HC. En conclusion, nos travaux de recherche ont permis d’identifier des vulnérabilités dans le microenvironnement immunitaire tumoral pouvant être ciblées dans la thérapie contre le CSHG.High-grade serous ovarian carcinoma (HGSOC) is the most aggressive and lethal subtype of ovarian cancer. Although better overall survival is associated with lymphocytic infiltration, immunotherapy by immune checkpoint blockades achieved modest results, reinforcing the importance of understanding immunity in this malignancy. Cancer immunity integrates innate and adaptive immune cells and makes use of inflammatory mediators to finely tune the magnitude and duration of the immune response. This thesis aims to reveal the heterogeneity of intratumoral and peripheral immune cells in ovarian cancer patients and explore the mechanisms of the immune response. For this purpose, we have used the high-resolution technology of single-cell RNAsequencing and computational biology to immune profile HGSOC patients. Firstly, we explored one of the mediators of inflammation, the immunosuppressive extracellular adenosine (eADO). The ectonucleotidases CD73 and CD39 regulate the eADO signaling pathway, and their expression is prognostic in several cancer types. Since their role in HGSOC was yet largely unexplored, we hypothesized that a transcriptomic meta-analysis of eADO signaling pathway would provide the clinical impact of the pathway in this malignancy. We analyzed the transcriptome of approximately 1200 HGSOC patients to evaluate the effect of CD39 and CD73 on clinical outcomes. While high expression of both ectonucleotidases was associated with worse overall survival in HGSOC, only CD39 was associated with chemoresistance, supporting the evaluation of eADO-targeting agents in HGSOC. Subsequently, we investigated T cell dynamics. Because T cell clones expanded in both tumor and peripheral tissue associated with response to ICB, we hypothesized that the tumor immune microenvironment (TIME) modulates their function and, therefore, analysis of cell-cell interaction would identify the cells participating in this process. Thus, we identified T cell states, inferred their developmental relationship, and studied transcriptional changes triggered by cellcell interactions in the TIME. We demonstrated that exhausted CD8 T cells highly expressed the chemokines CCL4 and XCL1, previously described in the priming of CD8 T cells in secondary lymphoid organs (SLOs). Finally, we proposed that the lipid mediator 7α,25 dihydroxycholesterol (7α,25-HC), only described in SLOs, may also modulate cell-cell interactions in the tumor immune microenvironment. Collectively, our studies propose strategies to modulate TIME in HGSOC targeting the adenosine pathway and oxysterols metabolites

Market value relevance of environmental, social and governance (ESG) scores

Mestrado Bolonha em FinançasThis study analyses the association between Corporate Social Responsibility (CSR) and market data, more concretely share prices and stock returns, for companies listed in the STOXX Europe 600 Index, from 2010 to 2019 period. To measure CSR was used the ESG (Environmental, Social, and Governance) overall score from Refinitiv and its three components: Environmental Score, Social Score, and Governance Score. The modified Ohlson model proposed by Barth and Clinch (2005) was used to study the price model, while the modified Ohlson model proposed by Ota (2005) was used to study the return model. Results suggest a positive association between CSR and market data, but in most models, especially in the price model, these are not statistically significant. Nevertheless, a statistically significant association between market data and changes in ESG scores was found. An additional robustness test suggests that the financial crisis impacted the relationship between CSR and market data. In the years affected by the crisis, investors are less concerned with sustainability issues.Este estudo analisa a relação existente entre o conceito de Responsabilidade Social (CSR) e dados de mercado, mais concretamente preços e retornos das ações, para empresas do Índice STOXX Europe 600, para o período de 2010 a 2019. Para medir a Responsabilidade Social, foi usado o indicador ESG proveniente da base de dados Refinitiv, bem como os seus três componentes: ambiental, social, e de governance. Foi usado o modelo modificado proposto por Barth and Clinch (2005) para estudar o modelo do preço, enquanto o modelo modificado proposto por Ota (2005) foi usado para estudar o modelo do retorno. Os resultados sugerem uma relação positiva entre a Responsabilidade Social e os dados de mercado, no entanto, na maioria dos modelos, especialmente no modelo do preço, esta relação não é significante. Apesar disso, existe uma relação significante entre os dados de mercado e a variável que representa as variações no ESG. Foi ainda aplicada uma análise de robustez que mostrou que a crise financeira teve impacto na relação entre as duas variáveis em estudo. Nos anos afetados pela crise, os investidores tornaram-se menos preocupados com aspetos ambientais.info:eu-repo/semantics/publishedVersio

On the measurement of US firms’ fixed operating costs

The objective of this study is to estimate the fixed operating costs of American firms using a novel measure that considers firms’ flexibility. In the sample, fixed operating costs account for 15.5% of the firm’s sales. The results show a significant level of heterogeneity across sectors of economic activity and firm size. In particular, it is found that the fixed operating costs to sales ratio is typically higher in smaller firms and service-related industries. This result is connected to the cost structure of firms in each sector. A negative correlation between the fixed operating costs to sales ratio and the share of COGS in total operating costs is found, as well as positive correlations between this ratio and the shares of SG&A expenses and depreciation and amortization. Lastly, the impact of the COVID-19 pandemic in this measure of fixed operating costs is studied. It is found that whenever the pandemic years are excluded from the regression, the fixed operating costs to sales ratios obtained are lower, on average, for the same dataset of firms and years.O objetivo deste estudo é estimar os custos operacionais fixos de empresas americanas utilizando uma nova medida que tem em consideração a flexibilidade da empresa. Na amostra, os custos operacionais fixos representam 15.5% das vendas da empresa. Os resultados evidenciam um nível significativo de heterogeneidade por setor de atividade económica e pelo tamanho da empresa. Em particular, conclui-se que o rácio de custos operacionais fixos para vendas é tipicamente maior em empresas mais pequenas e em indústrias relacionadas com os serviços. Este resultado está ligado à estrutura de custos das empresas em cada setor. Existe uma correlação negativa entre o rácio de custos operacionais fixos para vendas e o peso dos Custos de Bens Vendidos, assim como correlações positivas entre este rácio e os pesos de Despesas com Vendas, Gerais e Administrativas e depreciação e amortização. Por fim, o impacto da pandemia de COVID-19 nesta medida de custos operacionais fixos é estudado. Conclui-se que quando os anos de pandemia são excluídos da regressão, os rácios de custos operacionais fixos para vendas obtidos são menores, em média, para a mesma amostra de empresas e anos

Promoting intergenerationality at casa pousio - what are the main health challenges faced by seniors and university students

AMUT’s mission is to foster the well-being of individuals by enhancing health and overall happiness. In response to the pressing challenges of housing affordability and social isolation in Portugal, Casa Pousio’s project emerged. It goes beyond typical housing, aiming to create a unique community where different generations collaborate, promoting intergenerationality. It seeks to revolutionise living, becoming Portugal’s first Blue Zone – a community where residents enjoy longer, healthier lives. This analysis explores potential activities for Casa Pousio’s communal spaces, encouraging intergenerational interactions and knowledge exchange, and assesses the project’s financial viability

Space models as a tool for sustainability development

Space Models are new space geometries that are created to emphasize the particularities of the geo-referenced data analysed. A Space Model integrates groups of regions that present similar behaviour attending to a specific characteristic. Each group represents a cluster aggregating regions that are similar regarding to the analysed characteristic, and regions in different clusters are as dissimilar as possible. This paper proposes the creation of Space Models, through the STICH (Space Models Identification Through Hierarchical Clustering) algorithm, as an alternative approach for data visualization, where the geometry of the maps is created from the data itself. Space Models are new space geometries that are created to emphasize the particularities of the analysed data, and integrate groups of regions that present similar behaviour attending to a specific characteristic. The achieved results are illustrated through a set of examples that are compared with conventional representations, showing that Space Models provide real added-value over conventional approaches, namely by facilitating the identification of peculiarities in the data.EPSILON Project, funded by the Information Society Technologies program from European Commission - IST-2001-32389

Transmission of Major Arboviruses in Brazil: The Role of Aedes aegypti and Aedes albopictus Vectors

Arthropod‐borne viruses (arboviruses) are transmitted to a mammalian host by an infected arthropod vector. More than 130 types of arboviruses are known to cause disease in susceptible vertebrate hosts and are responsible for some of the most explosive epidemics of emerging infectious diseases in recent decades. The transmission cycle requires three essential components: virus, vector and vertebrate. Understanding the role of the vector in the arboviruses transmission is critical to improve emerging arbovirus disease control strategies. Since 2015, Brazil is faced with the challenge of three co-circulating arboviruses of major public health importance. Dengue virus (DENV) infection has been a public health for 30 years, which has suffered several epidemics caused by all four serotypes. The emergence of Chikungunya virus (CHIKV) and Zika virus (ZIKV) in Brazil poses new challenges to clinicians and public health authorities. In urban and suburban areas, those arboviruses are transmitted between people by Aedes mosquitoes in the subgenus Stegomyia, especially Ae. aegypti (the main vector) and potentially Ae. albopictus. Factors relating to the environment and the vector‐virus interactions can influence the dynamics of arboviruses transmission. This chapter describes the main biology aspects of the Ae. aegypti and Ae. albopictus that can influence the success of the transmission of main arboviruses in Brazil and provide information to understand the role of those factors in this dynamic relation